Discovery of the First Highly M5-Preferring Muscarinic Acetylcholine Receptor Ligand, an M5 Positive Allosteric Modulator Derived from a Series of 5-Trifluoromethoxy N -Benzyl Isatins

This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca(2+) mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.